Capillary separation techniques place stringent requirements on chromatographic detection systems. Detectors for separation techniques, such as capillary liquid chromatography, capillary supercritical fluid chromatography, and capillary zone electrophoresis, are required to measure minute amounts of the analytes. Detectors must have sub-nanoliter cell volumes to avoid efficiency and resolution loss due to solute band-broadening. Currently, low volume detectors that have high sensitivity and retain the integrity of the highly efficient separation are not commercially available. Thermo-optical absorbance measurements can be used to make very sensitive absorbance determinations within picoliter volume cells. The proposed research will develop on thermo-optical absorbance technique for detection in capillary chromatography. In Phase I, the feasibility of the picoliter laser-based absorbance/refractive index (RI) detector for highly sensitive low volume analyte detection in capillary based flowing systems will be investigated. In Phase II, the detector will be interfaced to capillary chromatographic systems for performance evaluations of the integrated system for analyses aimed at elucidating biomolecular and cellular structure and function. The overall goal of the proposal is to develop a commercial picoliter volume, thermo-optical detector for capillary chromatographic systems.